The envelope protein from the human immunodeficiency virus (gp120) has been shown to produce neurotoxicity in both cell cultures derived from the rodent CNS and in the brain of rodents. Administration of purified gp120 to developing rats produced delays in developmental milestones, particularly those involved in motor behavior. Widespread cerebral cortical neurodystrophy was apparent in neonates treated with gp120. These effects were produced by systemic administration of the gp120. To test for the biodistribution of gp120 after subcutaneous administration, highly purified envelope protein was radiolabeled. Fragments of gp120 were recovered in the brains of one-day-old rats given the labeled gp120 systemically. Only trace amounts of intact gp120 could be recovered in the brain. The labeled fragments of gp120 that were recovered in brain homogenates were found to exhibit neuronal toxicity in dissociated cerebral cortical cultures obtained from rats. The toxicity associated with the gp120 fragments were potently and completely prevented by co- treatment with peptide T in culture assay. Thus, these data indicate the intact gp120 is not necessary to produce neurotoxicity and that low molecular fragments of gp120 may play an important role in the etiology of neuro-AIDS. Furthermore, these data further establish that peptide T can prevent not only toxicity produced by gp120, but also that caused by gp120 fragments. The labeled gp120 was also found to be unstable. Upon storage at zero degrees, significant deterioration of labeled gp120 was observed within one month. Intact gp120 was recovered in culture medium after a 3-day exposure to cerebral cortical cultures. Deglycosylated gp120 was found to produce neurotoxicity, albeit at lower potency than that observed with the native glycosylated form.